Interleukin 6 (“IL6”) is a pleiotropic cytokine that regulates host immune responses, inflammation, hematopoiesis, and oncogenesis. IL6 biology is mediated by a multicomponent molecular system with two distinct modes of signaling operative on overlapping but non-identical cell populations. These are referred to as cis-signaling (also known as “classical” signaling) and trans-signaling.
In cis-signaling, IL6 binds to cell surface IL6 receptor, the ligand binding part of IL6R that is referred to as IL6Rα or CD126 (previously called gp80). The cell-bound IL6|IL6Rα complex in turn binds to non-ligand binding but signal transducing membrane protein gp130 (also known as IL6ST, IL6Rβ, or CD130), which induces gp130 dimerization and initiation of signaling. Thus, cis-signaling is restricted to the subset of cell types that express cell-surface IL6Rα, which is generally limited to, for example, mitogen-activated B cells, T cell subsets, peripheral monocytes, and certain tumors. The resultant ternary complex on the cell surface assembles into a very stable hexamer with a 2:2:2 ratio of IL6:IL6Rα:gp130 (Boulanger et al. (2003) Science 300:2101).
In trans-signaling, soluble IL6Rα (“sIL6Rα”) complexes with IL6 and the resulting circulating sIL6xR complex can bind to and activate any gp130-expressing cell (but not cells also expressing IL6Rα, Taga et al. (1989) Cell 58:573). Many, perhaps all or nearly all, cells in the human body express gp130. Because gp130 is ubiquitous, trans-signaling can affect many cell types and thereby sometimes cause disease.
The membrane protein gp130 also exists in soluble form (“sgp130”), which can bind sIL6xR complex in circulation. But, the sIL6xR complex binds equally well to membrane and soluble gp130 (see Jones et al, (2005) J. Interferon Cytokine Res. 25:241). Therefore, a molar excess of sgp130 can inhibit trans-signaling (by reducing the amount of available sIL6xR complex in circulation), which will not significantly affecting cis-signaling because the affinity of sgp130 is orders of magnitude less, as compared to cell surface gp130, for cell-bound IL6|IL6Rα complex (see, e.g., Jostock et al. (2001) Eur. J. Biochem. 268:160). Thus, it has been suggested that spg130 may be useful in inhibiting IL6 activity (see, e.g., Jostock et al. (2001) Eur. J. Biochem. 268:160). But, in addition to IL6, gp130 is a common signal-transducing protein for a family of gp130 cytokines. These include leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), neuropoietin (NP), cardiotropin like cytokine (CLC), oncostatin M (OSM), IL-27, IL-31 and cardiotrophin-1 (CT-1). Hence, although sgp130 can inhibit trans-signaling, administering such a compound to patients may have some unintended adverse effects.
Increased production of IL6 has been implicated in various disease processes, including Alzheimer's disease, autoimmunity (e.g., rheumatoid arthritis, SLE), inflammation, myocardial infarction, Paget's disease, osteoporosis, solid tumors (e.g., colon cancer, RCC prostatic and bladder cancers), certain neurological cancers, B-cell malignancies, such as Castleman's disease, some lymphoma subtypes, CLL, and, in particular, multiple myeloma. In some instances, IL-6 is implicated in proliferation pathways because it acts with other factors, such as heparin-binding epithelial growth factor and hepatocyte growth factor.
Several IL6 and IL6Rα antibody antagonists are known. For example, for IL6, Way et al. (US Patent Application Publication No. 2007/0178098) disclose antibodies against IL6 to sterically block IL6 or sIL6xR complex from binding to gp130 (see also U.S. Pat. No. 7,291,721). For example, for IL6Rα, Kishimoto (U.S. Pat. No. 5,670,373) discloses antibodies against IL6Rα that inhibit IL6 activity.